This proposal is submitted in response to PA-07-089. Despite its overall success at restoring immune function and often cognitive function in demented HIV-1-infected persons, highly active antiretroviral therapy has limited effects upon milder CNS disease that is increasingly prevalent. Based on our findings of treatment independent, significant gene dysregulation in brains of patients with minor cognitive and motor disorder (MCMD), we hypothesize that there are core changes in brain physiology arising from long-lived infected cells that persist through existing therapies, which were not designed to arrest expression of integrated provirus. Unabated production of viral proteins by these cells can cause cumulative inflammatory, antiviral, and oxidative stress reactions that affect neuronal function. To test this hypothesis as well as one mechanism underlying the core defect we propose four Specific Aims to: 1) establish genome-wide brain gene expression profiles representative of patients with milder forms of HIV CNS disease; 2) identify biological pathways and biomarkers in the brain characteristic of continuing mild HIV CNS disease in the presence of antiretroviral treatment; 3) validate selected markers of mild HIV CNS disease in a mouse model of HIV infection in immunocompetent and immunodeficient mice; 4) test the hypothesis that mild, chronic HIV CNS disease depends upon low level virus transcription unaffected by existing antiretroviral treatment. We rely upon brain tissue from well defined patient cohorts assembled by Dr. S. Morgello, gene discovery through genome wide expression analysis and bioinformatics, confirmatory studies including pathways of oxidative stress visible in lipid metabolites with Dr. Haughey, and a robust experimental model of HIV infection in mice that reproduces many features of mild CNS disease. Using chimeric HIV that can infect mice and is amenable to genetic modification, we shall test one causal hypothesis for mild CNS disease: low-level virus transcription that persists in the brain despite effective therapy maintains dysregulation of brain cell physiology that is expressed as MCMD. If these studies demonstrate that low level HIV-1 expression impairs cellular function in the brain despite antiviral treatment, efforts should be directed toward development of new antiviral agents to block viral transcription from cellular reservoirs. PUBLIC HEALTH RELEVANCE Medical science has prolonged life and improved health of HIV-infected people through development of effective antiviral drugs. Nevertheless, some aspects of HIV disease persist despite treatment, one of these leads to functional abnormalities in the brain and central nervous system. We propose to determine the molecular bases of this mild, but significant and persistent brain disease using state-of-the-art gene discovery and lipid metabolomics tools. Once confirmed in human beings, we shall use these markers of mild brain disease to test whether a similar disease caused by HIV infection of mice persists in the presence of drug treatment, even when the virus infection begins in the brain. Finally, we shall ask questions about the origin of mild brain disease in HIV infected people with effective therapy by establishing an experimental HIV infection in the brains of mice that is silent until it is turned on. By turning on and off this brain HIV, we shall determine whether it is residual HIV expression itself that causes the mild disease in the brain that cannot be controlled by existing drugs. This research may lead to two recommendations for control of the HIV CNS impairment that persists under current HAART regimes: a) earlier antiviral intervention relative to seroconversion than it is customary today; b) a call to the scientific and pharmaceutical communities to develop anti-HIV drugs that stop HIV expression.